An opioid antagonist is a receptor antagonist that acts on opioid receptors. Naloxone and naltrexone are commonly used opioid antagonists which are competitive antagonists that do not activate the receptors. This effectively blocks the receptor, preventing the body from responding to opiates and endorphins.
Some opioid antagonists are not pure antagonists but in fact do produce some weak opioid partial agonist effects, and can produce analgesic effects when administered in high doses to opioid-naive individuals. Examples of such compounds include nalorphine and levallorphan.
The weak partial agonist effect can be useful for some purposes, and has previously been used for purposes such as long-term maintenance of former opioid addicts using nalorphine, however it can also have disadvantages such as worsening respiratory depression in patients who have overdosed on non-opioid sedatives such as alcohol or barbiturates. Naloxone on the other hand has no partial agonist effects, and is in fact a partial inverse agonist at μ opioid receptors, and so is the preferred antidote drug for treating opioid overdose.
Naltrexone is also a partial inverse agonist, and this property is exploited in treatment of opioid addiction, as a sustained course of low-dose naltrexone can reverse the altered homeostasis which results from long-term abuse of opioid agonist drugs.
Buprenorphine is an opioid with both partial agonist and antagonist actions. Nor-binaltorphimine (nor-BNI) is a selective κ-opioid receptor antagonist.
Nalmefene [17-(cyclopropylmethyl)-4,5-alpha-epoxy-6-methylenemorphinan-3,14-diol], an example of an opioid antagonist, has the following general molecular formula:
and can be prepared using methods that are well known in the art e.g. from manufacturing naltrexone from noroxymorphone as described in WO 2012/059103 and subsequently manufacturing nalmefene from naltrexone e.g. by the Wittig reaction as described in WO 2010/136039. Nalmefene hydrochloride dihydrate is disclosed in WO 2010/136039.
Nalmefene is an opioid system modulator with a distinct μ, δ, and κ receptor profile. In vitro studies have demonstrated that nalmefene is a selective opioid receptor ligand with antagonist activity at the μ and δ receptors and partial agonist activity at the κ receptor.
The major feature of nalmefene is it's activity on K-opioid receptors with Ki/EC 50 of 1.6 nM. On μ-opioid receptors and δ-opioid receptors the activities are (Ki/EC 50 of 1.8 nM) and (Ki/EC 50 of 40 nM), respectively. The understanding of the role of the kappa opioid system in mediating mood has grown substantially in the last decade. Kappa-selective opioid agonists, including U-69593 and U-50488, produce anhedonia and a prodepressive phenotype in rodent models, including intracranial self-stimulation and forced swim test. In humans, kappa agonist administration (e.g., MR 2034 or salvinorin A) produces robust dissociative effects and cognitive disruption that partially, but not completely, overlap with symptoms associated with classic serotonergic hallucinogens. Moreover, the prodepressive phenotype produced by stress or kappa receptor activation in rodents is blocked by kappa antagonists or by genetic deletion of dynorphin or the kappa opioid receptor.
The efficacy and tolerability of nalmefene in the treatment of alcohol dependence have been evaluated in three phase III studies (two confirmatory 6-month efficacy studies and one 1-year safety study) conducted by Lundbeck (Mann et al. Extending the Treatment Options in Alcohol Dependence: A Randomized Controlled Study of As-Needed Nalmefene. Biol. Psychiatry. (2013) 73 (8): 706-713); Gual et al. A randomised, double-blind, placebo-controlled, efficacy study of nalmefene, as-needed use, in patients with alcohol dependence. Eur. Neuropsychopharmacol. (2013) 11: 1432-1442); and five studies in alcohol use disorders conducted by the company Biotie (Karhuvaara et al. Alcohol. Clin Exp Res. (2007) 31: 1179-1187).
A marketing authorisation was granted in the European Union (EU) in February 2013 for oral nalmefene (tradename Selincro®) for the reduction of alcohol consumption in adult patients with alcohol dependence who have a high drinking risk level (DRL), without physical withdrawal symptoms and who do not require immediate detoxification.
Vortioxetine [1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine] has the following general molecular formula:
International patent applications including WO 03/029232 and WO 2007/144005 disclose vortioxetine and pharmaceutically acceptable salts thereof. Vortioxetine was formerly referred to in the literature as LU AA 21004.
Vortioxetine is an antagonist on the 5-HT3, 5-HT7 and 5-HT1D receptors, an agonist on the 5-HT1A receptor and a partial agonist on the 5-HT1B receptor and an inhibitor of the serotonin transporter. Additionally, vortioxetine has demonstrated to enhance the levels of the neurotransmitters serotonin, noradrenalin, dopamine, acetylcholine and histamine in specific areas of the brain. All of these activities are considered to be of clinical relevance and potentially involved in the mechanism of action of the compound (J.Med.Chem. (2011), 54: 3206-3221; Eur. Neuropshycopharmacol. (2008), 18(suppl 4): S321; Eur. Neuropshycopharmacol. (2011), 21(suppl 4): S407-408; Int. J. Psychiatry Clin Pract. (2012), 5: 47).
Vortioxetine has in clinical trials shown to be a safe and efficacious treatment for depression. The results from a proof-of-concept study to evaluate the efficacy and tolerability of the compound in patients with major depressive disorder (MDD) was described by Alvares et al. A double-blind, randomized, placebo-controlled, active reference study of Lu AA 21004 in patients with major depressive disorder. Int. J. Neuropsychopharmacol. (2012); 15 (5): 589-600). The results from the six weeks, randomised, placebo-controlled study with approximately 100 patients in each arm show that vortioxetine separates significantly from placebo in the treatment of depressive and anxious symptoms in patients with MDD. It is also reported that no clinically relevant changes were seen in the clinical laboratory results, vital signs, weight, or ECG parameters. Results from a long-term study also show that vortioxetine is effective in preventing relapse in patients suffering from MDD (Eur. Neuropsychopharmacol. 21 (suppl 3), S396-397, 2011). A study in elderly depressed patients reported in Int. Clin. Psychopharm. (2012), 27: 215-227 shows that vortioxetine may be used to treat cognitive dysfunctions.
In September 2013 FDA approved vortioxetine for the treatment of major depressive disorder under the trade name Brintellix™.
Major depression, characterized by negative mood, reduced motivation, and sometimes anhedonia and decreased energy, affects nearly 5 % of people worldwide each year. Current antidepressants work well for some patients, but ˜60% suffer from unresolved residual symptoms or inadequate treatment response.
In the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-V), American Psychiatric Association, 2013; depressive disorder with melancholic features is characterized by e.g.:    A. One of the following:            1. Loss of pleasure in all, or almost all activities;        2. Lack of reactivity in usually pleasurable stimuli (does not feel better even when something good happens);            B. Three or more of the following:            1. Profound despondency, despair        2. Depression that is regularly worse in the morning        3. Early-morning awakening        4. Market psychomotor retardation or agitation        5. Significant anorexia or weight loss        6. Excessive or inappropriate guilt.        
The specifier “with melancholic features” is applied if these features are present at the most severe stage of the episode. There is a near-complete absence of the capacity for pleasure, not merely a diminution. A guideline for evaluating the lack of reactivity of mood is that even highly desired events are not associated with marked brightening of mood. Either mood does not brighten at all, or it brightens only partially (e.g., up to 20%-40% of normal for only minutes at a time). The “distinct quality” of mood that is characteristic of the “with melancholic features” specifier is experienced as qualitatively different from that during a nonmelancholic depressive episode. A depressed mood that is described as merely more severe, longer lasting, or present without a reason is not considered distinct in quality. Psychomotor changes are nearly always present and are observable by others. Melancholic features exhibit only a modest tendency to repeat across episodes in the same individual. They are more frequent in inpatients, as opposed to outpatients; are less likely to occur in milder than in more severe major depressive episodes; and are more likely to occur in those with psychotic features (Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-V), American Psychiatric Association, 2000).
Co-morbidity of alcohol dependence and depressive disorders are common and primarily based on findings from epidemiological studies which illustrate the complexity of the comorbidity between alcohol dependence on one side and mood disorders on the other side (Grant and Hartford, Drug and Alcohol Dependence, (1995), Vol. 39: 197-206.; Swendsen et al., Comprehensive Psychiatry, (1998), Vol. 38(4): 176-184; Swendsen and Merikangas, Clin. Psychol. Rev., (2000), Vol. 20(2):173-189; Kessler et al., Arch. Gen. Psychiatry, (1997), Vol. 54: 313-321).
These studies have also shown that there is a high level of lifetime comorbidity between depressive disorders and alcohol dependence. Patients with depressive disorders have an increased risk of suffering from alcohol dependence compared to patients without depression. Likewise, patients with alcohol dependence have an increased risk of comorbid depressive disorders compared to patients without alcohol dependence.
A recent study estimated that 16% of depressed patients also have a diagnosable addiction disorder (Sher et al., J. Clin. Psychiatry, 69 (2008), pp. 907-915). Such comorbidity puts patients at greater risk. Comorbid substance use in depressed patients is associated with greater symptom severity, inadequate treatment response, poorer prognosis (including increased risk of suicide), and persistence of depressive symptoms (Thase et al., J. Clin. Psychiatry, 62 (Suppl. 20) (2001), pp. 32-41 and Blanco et al., J. Clin. Psychiatry, 73 (2012), pp. 865-873). Therefore, a tremendous need exists for pharmacotherapies effective in treating both depressive symptoms and alcohol dependence.
κ-opioid receptors and their endogenous neuropeptide ligand, dynorphin A, are densely localized in limbic and cortical areas comprising the brain reward and stress systems, and play a key role in modulating neurotransmission in these areas. In preclinical models, stress produces a prodepressive phenotype that is believed to be associated with the activation of κ-opioid receptors and subsequent downstream signaling events. Stressful effects (stress) increase the release of dynorpin, an endogenous ligand of κ-opioid receptor (Knoll and Carlezon, Brain Res. (2010), 1314: 56-73). Activation of κ-opioid receptors by dynorphin will decrease dopamine concentration in the nucleus accumbens, resulting in anhedonic symptoms of depression. A κ-opioid receptor antagonist administration will alleviate this effect.
Consistent with this hypothesis, kappa receptor agonists produce anxiogenic- and prodepressive-like effects in animals and humans (Pfeiffer A, Brantl V, Herz A, Emrich HM (1986), Science 233: 774-776 P and Todtenkopf M S, Marcus J F, Portoghese P S, and Carlezon W A Jr (2004), Psychopharmacology 172:463-470, but see also M. T. Harden, S. E. Smith, J. A. Niehoff, C. R. McCurdy, G. T. Taylor (2012), Behavioural Pharmacology, 23 (7) pp. 710-715, whereas kappa receptor antagonists reliably exhibit antidepressant-like effects in animal models predictive of efficacy in the domains of mood and affect (Mague S D, Pliakas A M, Todtenkopf M S, Tomasiewicz H C, Zhang Y, Stevens W C Jr, Jones R M, Portog-hese P S, and Carlezon W A Jr (2003), J Pharmacol Exp Ther 305:323-330; B. B. Land, M. R. Bruchas, S. Schattauer, W. J. Giardino, M. Aita, D. Messinger (2009), PNAS 106 (45) pp. 19168-19173 and Carr G V, Bangasser D A, Bethea T, Young M, Valentino R J, Lucki I (2010), Neuropsycho-pharmacology 35:752-763).
While some opioid antagonists are efficacious in animal models of alcoholism, they do not produce reliable antidepressant- or anxiolytic-like effects in animals or humans, likely due to functional opposition between mu and kappa receptors. Similarly, antidepressants are weakly and inconsistently effective at reducing alcohol consumption in depressed patients with comorbid addictive disorders. Because kappa antagonists demonstrate efficacy in animal models predictive of efficacy in mood and addictive disorders, they have the potential to treat depressed patients with comorbid alcohol dependence.
There is a need for new treatments for use in patients with depressive disorder with melancholic features. Furthermore, there is a need for new treatments for use in patients with alcohol dependence who have depressive disorder with melancholic features. In particular, there is a need for new treatments which could give rise to advantages such as e.g. improved efficacy and/or a different side effect profile compared to existing treatments.